Increased oxidative stress and severe arterial remodeling induced by permanent high-flow challenge in experimental pulmonary hypertension

Atopic asthma is a chronic inflammatory pulmonary disease characterised by recurrent episodes of wheezy, laboured breathing with an underlying Th2 cell-mediated inflammatory response in the airways. It is currently treated and, more or less, controlled depending on severity, with bronchodilators e.g. long-acting beta agonists and long-acting muscarinic antagonists or anti-inflammatory drugs such as corticosteroids (inhaled or oral), leukotriene modifiers, theophyline and anti-IgE therapy. Unfortunately, none of these treatments are curative and some asthmatic patients do not respond to intense anti-inflammatory therapies. Additionally, the use of long-term oral steroids has many undesired side effects. For this reason, novel and more effective drugs are needed. In this review, we focus on the CD4+ Th2 cells and their products as targets for the development of new drugs to add to the current armamentarium as adjuncts or as potential stand-alone treatments for allergic asthma. We argue that in early disease, the reduction or elimination of allergen-specific Th2 cells will reduce the consequences of repeated allergic inflammatory responses such as lung remodelling without causing generalised immunosuppression.     

Treatment of allergic asthma: Modulation of Th2 cells and their responses

Atopic asthma is a chronic inflammatory pulmonary disease characterised by recurrent episodes of wheezy, laboured breathing with an underlying Th2 cell-mediated inflammatory response in the airways. It is currently treated and, more or less, controlled depending on severity, with bronchodilators e.g. long-acting beta agonists and long-acting muscarinic antagonists or anti-inflammatory drugs such as corticosteroids (inhaled or oral), leukotriene modifiers, theophyline and anti-IgE therapy. Unfortunately, none of these treatments are curative and some asthmatic patients do not respond to intense anti-inflammatory therapies. Additionally, the use of long-term oral steroids has many undesired side effects. For this reason, novel and more effective drugs are needed. In this review, we focus on the CD4+ Th2 cells and their products as targets for the development of new drugs to add to the current armamentarium as adjuncts or as potential stand-alone treatments for allergic asthma. We argue that in early disease, the reduction or elimination of allergen-specific Th2 cells will reduce the consequences of repeated allergic inflammatory responses such as lung remodelling without causing generalised immunosuppression.     

Adenosine, an endogenous distress signal, modulates tissue damage and repair

Adenosine is formed inside cells or on their surface, mostly by breakdown of adenine nucleotides. The formation of adenosine increases in different conditions of stress and distress. Adenosine acts on four G-protein coupled receptors: two of them, A(1) and A(3), are primarily coupled to G(i) family G proteins; and two of them, A(2A) and A(2B), are mostly coupled to G(s) like G proteins. These receptors are antagonized by xanthines including caffeine. Via these receptors it affects many cells and organs, usually having a cytoprotective function. Joel Linden recently grouped these protective effects into four general modes of action: increased oxygen supply/demand ratio, preconditioning, anti-inflammatory effects and stimulation of angiogenesis. This review will briefly summarize what is known and what is not in this regard. It is argued that drugs targeting adenosine receptors might be useful adjuncts in many therapeutic approaches.     

Small molecule compounds with good anti-inflammatory activity reported in the literature from 01/2009 to 05/2021: a review

Inflammation and disease are closely related. Inflammation can induce various diseases, and diseases can promote inflammatory response, and two possibly induces each other in a bidirectional loop. Inflammation is usually treated using synthetic anti-inflammatory drugs which are associated with several adverse effects hence are not safe for long-term use. Therefore, there is need for anti-inflammatory drugs which are not only effective but also safe. Several researchers have devoted to the research and development of effective anti-inflammatory drugs with little or no side effects. In this review, we studied some small molecules with reported anti-inflammatory activities and hence potential sources of anti-inflammatory agents. The information was retrieved from relevant studies published between January 2019 and May, 2021 for review. This review study was aimed to provide relevant information towards the design and development of effective and safe anti-inflammation agents.     

Neuroprotective effects of non-steroidal anti-inflammatory drugs by direct scavenging of nitric oxide radicals

Recently, it has been reported that inflammatory processes are associated with the pathophysiology of Alzheimer's disease and that treatment of non-steroidal anti-inflammatory drugs reduce the risk for Alzheimer's disease. In the present study, we examined nitric oxide radical quenching activity of non-steroidal anti-inflammatory drugs and steroidal drugs using our established direct in vitro nitric oxide radical detecting system by electron spin resonance spectrometry. The non-steroidal anti-inflammatory drugs, aspirin, mefenamic acid, indomethacin and ketoprofen directly and dose-dependently scavenged generated nitric oxide radicals. In experiments of nitric oxide radical donor, NOC18-induced neuronal damage, these four non-steroidal drugs significantly prevented the NOC18-induced reduction of cell viability and apoptotic nuclear changes in neuronal cells without affecting the induction of inducible nitric oxide synthase-like immunoreactivity. However, ibuprofen, naproxen or steroidal drugs, which had less or no scavenging effects in vitro, showed almost no protective effects against NOC18-induced cell toxicity. These results suggest that the protective effects of the former four non-steroidal anti-inflammatory drugs against apoptosis might be mainly due to their direct nitric oxide radical scavenging activities in neuronal cells. These direct NO. quenching activities represent novel effects of non-steroidal anti-inflammatory drugs. Our findings identified novel pharmacological mechanisms of these drugs to exert not only their anti-inflammatory, analgesic, antipyretic activities but also neuroprotective activities against neurodegeneration.     

Influence of non-steroidal anti-inflammatory drugs on the outcome of faecal occult blood tests in screening for colorectal cancer.

Non-steroidal anti-inflammatory drugs have been accused of causing false positive results in faecal occult blood tests for colorectal cancer. A study was therefore performed in 10,931 people undergoing faecal occult blood screening tests to assess the effect of these drugs on the predictive value of a positive test result. Those with a positive result were interviewed and a full drug history was taken before they underwent a full colorectal examination. Of the 455 people with a positive result, 50 were taking non-steroidal anti-inflammatory drugs: 10 (20%) had colonic neoplasia. Of the 405 who were not taking non-steroidal anti-inflammatory drugs, 129 (32%) had colonic neoplasia. These detection rates were not significantly different, and the predictive value of a positive result for an adenoma larger than 1 cm was 14% in the group not taking anti-inflammatory drugs and 26% in the group taking them (not significant). These results suggest that a finding of occult faecal blood cannot be attributed to upper gastrointestinal tract bleeding caused by non-steroidal anti-inflammatory drugs and should be followed by a thorough colorectal examination.     

Use of anti-inflammatory drugs by patients admitted with small or large bowel perforations and haemorrhage.

The intake of anti-inflammatory drugs by 268 patients with colonic or small bowel perforation or haemorrhage was compared with that by a group of patients, matched for age and sex, with uncomplicated lower bowel disease. Patients with perforation or haemorrhage were more than twice as likely to be takers of anti-inflammatory drugs, but no association was detected with the intake of other types of drugs, particularly cardiovascular drugs. The association between complicated lower bowel disease and intake of anti-inflammatory drugs may be causal.     

The risk of upper gastrointestinal complications associated with nonsteroidal anti-inflammatory drugs, glucocorticoids, acetaminophen, and combinations of these agents

Most anti-inflammatory drugs have been associated with an increased risk of serious upper gastrointestinal complications. Epidemiological studies have estimated the magnitude of the risk for specific anti-inflammatory drugs. The risk of upper gastrointestinal tract bleeding or perforation increases around twofold with use of oral steroids or low dose aspirin, and increases around fourfold with use of nonaspirin nonsteroidal anti-inflammatory drugs. Acetaminophen at daily doses of 2000 mg and higher has also been associated with an increased risk. Overall, the risk is dose dependent and is greater with more than one anti-inflammatory drug taken simultaneously. Hence, whenever possible, anti-inflammatory drugs should be given in monotherapy and at the lowest effective dose in order to reduce the risk of serious upper gastrointestinal complications.     

抗炎药物用于 2 型糖尿病预防与治疗的研究进展

近年来,炎症反应在2型糖尿病发病机制中的作用受到广泛关注。流行病学和实验动物研究均证明,肥胖及其诱发的慢性炎症 与2型糖尿病有密切的关系。基于诸多临床流行病学调查及大型前瞻性研究结果,目前已形成对糖尿病胰岛素耐受性的炎症发病机制的 共识。到目前为止,多种具有抗炎作用机制的活性小分子药物已经上市或进入临床研究阶段,这些药物单独治疗或与传统降糖药物联用 均取得了令人满意的效果,显示了糖尿病抗炎治疗的前景。主要综述近年来慢性炎症在2型糖尿病发生发展过程中的分子机制以及抗炎 药物用于治疗2型糖尿病的研究进展     

COX-2: Where are we in 2003? - Specific cyclooxygenase-2 inhibitors and aspirin-exacerbated respiratory disease

The use of analgesic anti-inflammatory agents in patients with asthma is clinically challenging because of the prevalence (10-20%) of aspirin hypersensitivity. Aspirin-exacerbated respiratory disease (AERD), or aspirin-induced asthma, is characterized by asthma and rhinitis triggered by the ingestion of aspirin and non-steroidal anti-inflammatory drugs. AERD is associated with upper and lower respiratory-tract mucosal inflammation, progressive sinusitis, nasal polyposis, and asthma regardless of whether patients avoid triggering drugs. The mechanism underlying the propensity of aspirin and non-steroidal anti-inflammatory drugs to cause this reaction is thought to involve inhibition of the synthesis of protective prostaglandins (PGs), resulting in an increase in the synthesis of cysteinyl leukotrienes by eosinophils and mast cells. Clinical data suggest that protective PGs are derived from cyclooxygenase (COX)-1 because studies have now confirmed that drugs specifically inhibiting COX-2 are not cross-reactive with aspirin in patients with AERD.     

COX-2: Where are we in 2003? - Specific cyclooxygenase-2 inhibitors and aspirin-exacerbated respiratory disease

The use of analgesic anti-inflammatory agents in patients with asthma is clinically challenging because of the prevalence (10–20%) of aspirin hypersensitivity. Aspirin-exacerbated respiratory disease (AERD), or aspirin-induced asthma, is characterized by asthma and rhinitis triggered by the ingestion of aspirin and non-steroidal anti-inflammatory drugs. AERD is associated with upper and lower respiratory-tract mucosal inflammation, progressive sinusitis, nasal polyposis, and asthma regardless of whether patients avoid triggering drugs. The mechanism underlying the propensity of aspirin and non-steroidal anti-inflammatory drugs to cause this reaction is thought to involve inhibition of the synthesis of protective prostaglandins (PGs), resulting in an increase in the synthesis of cysteinyl leukotrienes by eosinophils and mast cells. Clinical data suggest that protective PGs are derived from cyclooxygenase (COX)-1 because studies have now confirmed that drugs specifically inhibiting COX-2 are not cross-reactive with aspirin in patients with AERD.     

Fatal peptic ulcer complications and the use of non-steroidal anti-inflammatory drugs,aspirin, and corticosteroids.

Although non-steroidal anti-inflammatory drugs are known to cause peptic ulcer and its complications, controversy exists about the number of deaths from ulcer which are attributable to their use. A case-control study was therefore performed to determine whether prior use of non-steroidal and other anti-inflammatory compounds was associated with an increased case fatality rate from complications of peptic ulcer. Non-steroidal anti-inflammatory drugs were used by 39% of a series of 80 patients who had died from peptic ulcer complications and by 37% of 160 controls who were survivors matched for sex, age, ulcer site, and nature of complication (odds ratio 1.1; 95% confidence interval 0.6 to 2.1). Similarly, the rates of prior use of aspirin by cases and controls were almost identical (odds ratio 1.2; 95% confidence interval 0.5 to 1.9). Thus neither nonsteroidal anti-inflammatory drugs nor aspirin were associated with increased case fatality rates from peptic ulcer complications. In contrast, corticosteroids were associated with an increased mortality (odds ratio 4.2; 95% confidence interval 0.9 to 25.6). Although this increase in the estimated relative risk was not statistically significant, a review of the case records indicated that most deaths in steroid users were due to serious sepsis, indicating that there might be a causal association between use of the drugs and the mode of death.     

Comparative pharmacokinetics of three non-steroidal anti-inflammatory drugs in five bird species

Information on the pharmacokinetics and pharmacodynamics of anti-inflammatory drugs in birds is scarce. Choice of drug and of dosage is usually empirical, since studies of anti-inflammatory drugs are lacking. In this study, three common veterinary non-steroidal anti-inflammatory drugs (NSAIDs) were administered intravenously to five different bird species. Sodium salicylate, flunixin and meloxicam were selected as anti-inflammatory drugs. These NSAIDs were administered intravenously to chickens (Gallus gallus), ostriches (Struthio camelus), ducks (Anas platyrhynchos), turkeys (Meleagris gallopavo) and pigeons (Columba livia). Plasma concentrations of the drugs were determined by validated high-performance liquid chromatography methods and pharmacokinetic parameters were calculated. Most bird species exhibited rapid elimination of these drugs. Ostriches had the fastest elimination rate for all three NSAIDs, but there were some interesting species differences. Chickens had a half-life that was approximately 10-fold as long as the other bird species for flunixin. The half-life of chickens and pigeons was three-fold as long as the other bird species for meloxicam, and, for salicylic acid, the half-life in pigeons was at least three-five-fold longer than in the other bird species.     

Aspirin and bleeding peptic ulcers in the elderly.

A case-control study was performed to determine whether aspirin confers a similar risk of bleeding from gastric or duodenal ulcers in the elderly as non-aspirin, non-steroidal anti-inflammatory drugs. The intake of analgesics in 230 patients with bleeding ulcers aged 60 and over and in hospital and community controls matched for age and sex was examined. Those who had taken aspirin were between two and three times more likely to be admitted to hospital with bleeding ulcers. This increased risk was not accounted for by aspirin taken for indigestion or by concurrent use of non-aspirin, non-steroidal anti-inflammatory drugs. A similar effect was not seen for paracetamol. When aspirin and other non-steroidal anti-inflammatory drugs were considered together the overall risk attributed to the drugs suggested that these drugs may be responsible for over a third of admissions for bleeding peptic ulcers in the elderly.     

Use of local anaesthetics and adjuncts for spinal and epidural anaesthesia and analgesia at German and Austrian University Hospitals: an online survey to assess current standard practice

Background

The present anonymous multicenter online survey was conducted to evaluate the application of regional anaesthesia techniques as well as the used local anaesthetics and adjuncts at German and Austrian university hospitals.

Methods

39 university hospitals were requested to fill in an online questionnaire, to determine the kind of regional anaesthesia and preferred drugs in urology, obstetrics and gynaecology.

Results

33 hospitals responded. No regional anaesthesia is conducted in 47% of the minor gynaecological and 44% of the urological operations; plain bupivacaine 0.5% is used in 38% and 47% respectively. In transurethral resections of the prostate and bladder no regional anaesthesia is used in 3% of the responding hospitals, whereas plain bupivacaine 0.5% is used in more than 90%. Regional anaesthesia is only used in selected major gynaecological and urological operations. On the contrary to the smaller operations, the survey revealed a large variety of used drugs and mixtures. Almost 80% prefer plain bupivacaine or ropivacaine 0.5% in spinal anaesthesia in caesarean section. Similarly to the use of drugs in major urological and gynaecological operations a wide range of drugs and adjuncts is used in epidural anaesthesia in caesarean section and spontaneous delivery.

Conclusions

Our results indicate a certain agreement in short operations in spinal anaesthesia. By contrast, a large variety concerning the anaesthesiological approach in larger operations as well as in epidural analgesia in obstetrics could be revealed, the causes of which are assumed to be primarily rooted in particular departmental structures.     

The anti-inflammatory activity of Enicostemma littorale and Mollugo cerviana

The anti-inflammatory activity of E. littorale and M. cerviana was assessed by carrageenan-induced inflammation and cotton pellet granuloma method in rats. E. littorale and M. cerviana exerted 54 and 26% anti-inflammatory activity for a dose of 100 mg/100 g body wt, respectively, in carrageenan-induced acute inflammation. In chronic inflammation of cotton pellet granuloma, E. littorale and M. cerviana exerted 30 and 46% anti-inflammatory activity at the above dosage, respectively. The optimal dose for these drugs was determined in carrageenan inflammation. The effect of the alcoholic extract of these drugs on human erythrocyte membrane stabilization and inhibition of cobra venom phospholipase A2 was studied in vitro and the drugs were found to be effective. Further, these drugs were found to inhibit the levels of lipid peroxides, acid phosphatase, and gamma-glutamyl transpeptidase activity in the exudate of cotton pellet granuloma. The effects were compared with those of standard anti-inflammatory drug, hydrocortisone. A possible mode of action of these drugs is suggested.     

Pharmacokinetics of non-steroidal anti-inflammatory drugs in male rabbits after acute and chronic administration and effect of chronic treatment on seminal prostaglandins, sperm quality and fertility

The pharmacokinetics of various non-steroidal anti-inflammatory drugs were determined to find dosage regimens by which drug concentrations known as active from human anti-inflammatory therapy could be reached and maintained in rabbits during continued administration. Based on the pharmacokinetics and side-effects of the different drugs, phenylbutazone was selected for the fertility experiments. Treatment of male rabbits with phenylbutazone for 9 consecutive days significantly reduced seminal concentrations of PGE-2 and PGF-2 alpha and tended to increase ejaculate volumes, sperm motility, and fertility. These results indicate that, at least in rabbits, inhibition of PG synthesis by prolonged treatment with non-steroidal anti-inflammatory drugs does not impair male fertility. Instead, chronic treatment with the drugs at non-toxic doses may improve sperm quality and fertility.